Dipeptidyl Peptidase 4 Inhibitors and Risk of Inflammatory Bowel Disease: Real-world Evidence in U.S. Adults

Abstract

Objective: A recent study raises concerns that dipeptidyl peptidase 4 inhibitors (DPP4i) are associated with increased risk of inflammatory bowel disease (IBD). We evaluated the association between new use of DPP4i and IBD risk compared with other second-line antihyperglycemics.

Research design and methods: We implemented an active-comparator, new-user cohort design using two U.S. administrative claims databases for commercially insured (MarketScan) and older adult (Medicare fee-for-service, 20% random sample) patients from January 2007 to December 2016. We identified patients, aged ≥18 years, who initiated DPP4i versus sulfonylureas (SUs) or initiated DPP4i versus thiazolidinediones (TZDs) and were without prior diagnosis, treatment, or procedure for IBD. The primary outcome was incident IBD, defined by IBD diagnosis preceded by colonoscopy and biopsy and followed by IBD treatment. We performed propensity score weighting to control for measured baseline confounding, estimated adjusted hazard ratios (aHRs [95% CI]) using weighted Cox proportional hazards models, and used random-effects meta-analysis models to pool aHRs across cohorts.

Results: We identified 895,747 eligible patients initiating DPP4i, SU, or TZD; IBD incidence rates ranged from 11.6 to 32.3/100,000 person-years. Over a median treatment duration of 1.09-1.69 years, DPP4i were not associated with increased IBD risk across comparisons. The pooled aHRs for IBD were 0.82 (95% CI 0.41-1.61) when comparing DPP4i (n = 161,612) to SU (n = 310,550) and 0.76 (0.46-1.26) when comparing DPP4i (n = 205,570) to TZD (n = 87,543).

Conclusions: Our population-based cohort study of U.S. adults with diabetes suggests that short-term DPP4i treatment does not increase IBD risk.

Figure 1

SMR-weighted Kaplan-Meier plots of IBD: DPP4i vs. SU cohort in MarketScan (A), DPP4i vs. SU cohort in Medicare (B), DPP4i vs. TZD cohort in MarketScan (C), and DPP4i vs. TZD cohort in Medicare (D). Follow-up started for the outcome 180 days (induction period) after the second prescription (cohort entry date). SMR weights create a pseudopopulation of the untreated (comparators: SU or TZD), which has the same covariate distribution as the treated (DPP4i). Every patient receiving DPP4i has a weight of 1, while every patient in the comparator group is weighted by (PS/[1 − PS]). The risks on the y-axis were obtained by SMR-weighted Cox model (weighting comparator drug initiators by the PS odds [PS/(1 − PS)]). HR treating comparators as reference; aHR <1 indicates a lower risk for DPP4i. Dotted lines around the survival curve point estimates represent 95% CI bands. *HR 1.08 (95% CI 0.70–1.68); †HR 0.53 (0.24–1.15); ‡HR 0.68 (0.37–1.26); §HR 0.97 (0.40–2.37).

Figure 2

Forest plot summarizing primary, secondary, and sensitivity analyses showing the association between initiating DPP4i and the risk of IBD compared with SU (A) and TZD (B), respectively. The effect estimate for each analysis is the pooled aHR from the two databases. ESRD, end-stage renal disease; GI, gastrointestinal; Rx, prescription.